Introduction

Few studies have examined esophageal motility disorders in patients with type 2 diabetes operated with sleeve gastrectomy (SG) or gastric bypass (RYGB).

Aims & Methods

We have recently reported overall prevalence of gastroesophageal reflux disease (GERD) in this group of patients (1) and now aimed to investigate potential differences between the two surgical methods regarding the prevalence of dysmotility 5 years after surgery. Furthermore, we also aimed to analyse and report on the available GERD-data in detail.
In the Oseberg study (January 2013 – December 2022), 125 patients with BMI ≥ 35 kg/m² and type 2 diabetes were screened, sixteen patients were excluded or withdrew consent, leaving 109 patients allocated to SG (n=55) or RYGB (n=54). To assess reflux symptoms, GerdQ (Gastroesophageal reflux disease questionnaire) was completed. Gastroscopy and 24-hour pH monitoring were used to examine GERD. High-resolution manometry with the Chicago classification v3.0 was used to assess esophageal motility.

Results

At inclusion the average age was 47.7 years (SD 9.6), BMI was 42.3 kg/m2 (5.3), and 66% were women. At the 5-year follow-up, 29 (53%) patients in SG-group and 32 (59%) in RYGB-group underwent gastroscopy, 22 (40%) vs. 25 (46%) underwent 24-hour pH monitoring, 23 (42%) vs. 26 (48%) underwent manometry, and 42 (76%) vs. 42 (78%) completed GerdQ. The proportion of patients with GERD symptoms (GerdQ ≥8) was low in both groups, with a slightly lower prevalence after RYGB (2%) than after SG (14%). There was no difference in the prevalence of erosive esophagitis between the groups (38% in SG and 41% in RYGB), all findings with less advanced esophagitis (Los Angeles grades A and B), but one patient in each group had new onset Barrett's esophagus. The proportion of patients with pH<4 for more than 6% of the recording (Acid exposure time, AET) was significantly higher after SG compared with RYGB (59% versus 8%, p < 0.0001). Esophageal dysmotility was diagnosed in 14 (61%) after SG compared with 19 (73%) patients after RYGB. Most of these patients (n=22) had hypertensive or hypotensive lower esophageal sphincter (LES), with no difference between groups. The remaining 11 patients had ineffective esophageal motility (IEM) or elevated distal contractile integral (DCI). None of the patients with dysmotility reported swallowing difficulties or chest pain with food intake.

Conclusion

The Oseberg study demonstrates a high prevalence of asymptomatic esophageal dysmotility after SG or RYGB with uncertain clinical relevance. Furthermore, a seven times higher prevalence of pathological acid reflux after SG compared with RYGB was demonstrated, but the prevalences of erosive esophagitis and esophageal dysmotility were approximately similar between groups. Few of the examined patients reported GERD symptoms, hence objective assessment of GERD should be included in long-term follow-up after SG to detect and prevent the development of Barrett's esophagus, dysplasia, and adenocarcinoma.

References

1. Hauge JW et al., Effect of gastric bypass versus sleeve gastrectomy on the remission of type 2 diabetes, weight loss, and cardiovascular risk factors at 5 years (Oseberg): secondary outcomes of a single-centre, triple-blind, randomised controlled trial. Lancet Diabetes Endocrinol. 2025 Apr 1:S2213-8587(24)00396-6

Introduction

Corpus atrophic gastritis (CAG) requires endoscopic-histological surveillance due to the risk of developing gastric neoplastic lesions (GNL). This study aimed to identify variables associated with GNL development at long-term follow-up using a feature ranking method based on a novel One-Class Support Vector Machine (SVM) model.

Aims & Methods

A dataset containing clinical, endoscopic, and histological variables from consecutive CAG patients (2001-2023) adhering to a surveillance program was considered. GNL presence at the longest available follow-up was recorded. Gastric biopsies and histological evaluations were conducted according to the updated Sydney system. CAG patients with any missing data or a GNL diagnosis at the baseline gastroscopy were excluded from the final analysis. A Fisher score-based feature ranking method and One-Class SVM were used to select the optimal subset of baseline variables associated with GNL development, aiming to achieve average sensitivity (Se) and specificity (Sp) above 80%.

Results

Overall, 355 CAG patients were initially considered. Of these, 36 were excluded due to the presence of GNL at baseline gastroscopy, and 216 for missing data. Thus, a total of 103 patients were considered and grouped into: CAG patients with [22 patients (F 68.1%), median age 68 (35-83) years] and without GNL at follow-up [81 patients (F 72.8%), median age 59(26-84) years]. After a median follow-up of 60 (12-192) months, 13 epithelial GNL (gastric adenocarcinoma or high/low-grade dysplasia) and nine type-1 gastric-neuroendocrine-tumors (T1gNET) were recorded. Parietal-cell-antibodies and pepsinogen-I < 30 μg/l were associated with both epithelial GNL and T1gNET. Antral inflammation and age > 60 were linked to epithelial GNL, while anti-thyroperoxidase-antibodies, smoking, and dyspeptic symptoms at CAG diagnosis were linked to T1gNET. Low-dose aspirin and H. pylori eradication therapy showed inverse associations with epithelial GNL and T1gNET, respectively.

Conclusion

This is the first study in which an AI model simultaneously considers clinical, endoscopic, and histological characteristics from a dataset of CAG patients, showing good sensitivity and specificity in identifying those variables associated with developing GNL. Nonetheless, we acknowledge the need for improved variable standardization and data balancing between groups to enhance model performance further.

Introduction

Current treatment options for IBD are limited by low clinical remission rates and loss of response. Most therapies target single pathogenic pathways and while combinations of biologics targeting different pathogenic cytokines can increase clinical remission rates, dosing schedules are inconvenient. JAK inhibitors, target multiple cytokine pathways, but are limited by safety concerns.
Salt-inducible kinases (SIKs) are a subfamily of serine/threonine kinases in the AMP-activated protein kinase (AMPK) family and act as key regulators of immune cell signaling. SIK inhibitors have been shown to target multiple cytokine pathways.
Three SIK isoforms exist: SIK1, SIK2 and SIK3. SIK inhibitors targeting multiple isoforms have been investigated in clinical trials. Although there have been signals of activity in patients with ulcerative colitis and psoriasis, limited efficacy and safety concerns related to SIK1 and 2 inhibition have hampered their development.

Aims & Methods

We performed structure based drug design to identify highly potent and selective SIK3 inhibitors that could offerbest in class efficacy and safety for the treatment of various auto-immune diseases. Our effort led to to the discovery of 100s of compounds spanning SIK3 binding sites. Compounds were tested in protein and cell-based assays to evaluate potency and selectivity against SIK3 and in a phenotypic human whole blood TNFα assay. Lead optimization involving rigorous testing in safety and pharmacology panels, resulted in the selection of lead candidates that were tested in a variety of translational models to identify the most efficacious compounds. Human PK predictions were performed using non-clinical in vivo PK assessments and allometric scaling leading to the selection of the drug candidate, which entered GLP toxicology studies.

Results

O3R-5671 is a highly potent and specific SIK3 inhibitor with sub-nanomolar potency for SIK3 and low activity against SIK1 and 2 and over all human kinases. It demonstrated potent activity in a panel of human primary phenotypic cell assays inhibiting TNFα, IL-12, and IL-23 release in LPS-stimulated myeloid cells, and inhibiting TNFa release in LPS-stimulated human whole blood. O3R-5671 also inhibited activation of TCR-stimulated human primary T cells and induced IL-10 secretion from myeloid cells.
In vivo, O3R-5671 demonstrated dose-dependent activity in a mouse LPS challenge model, dose-dependent efficacy in two distinct mouse models of IBD, and dose-dependent efficacy in mouse models of IL-23-induced psoriasis and psoriatic arthritis. Cross-species PK and allometric scaling were used to predict O3R-5671’s human PK profile- which is expected to be conducive to potent SIK3 inhibition and clinical efficacy in patients with IBD.
O3R-5671 demonstrated a highly attractive profile in ADME and in vitro safety panels. Six-week GLP toxicity studies in rats and dogs established no observed adverse effect levels (NOAELs) which support dosing in humans with doses that are predicted to be pharmacologically active with a large safety margin.

Conclusion

O3R-5671 is a highly specific and potent SIK3 inhibitor that is predicted to have a flat PK profile in humans. These properties should allow O3R-5671 to apply strong drug pressure on SIK3 while sparing SIK1 and 2. This is expected to result in the inhibition of multiple pathogenic cytokines including TNFa and IL-23, both of which have been validated as IBD targets. A clinical trial is ongoing to establish the safety and PK profile of O3R-5671 and understand its effect on pharmacodynamic biomarkers.

Disclosure

All authors were employed by Galapagos who discovered O3R-5671 or Novalix, a CRO that was employed by Galapagos. Some authors are employed by Onco3R therapeutics, who are currently developing O3R-5671